The resolution of racemates constitutes the main method for industrial preparation of pure enantiomers. Methods for such resolution include: direct preferential crystallization; crystallization of the diastereomeric salts; kinetic resolution; and asymmetric synthesis.
Also referred to as resolution by entrainment, preferential crystallization is widely used on an industrial scale; for example, in the manufacture of .alpha.-methyl-L-dopa and chloramphenicol. It is technical feasible only with racemates which are so-called conglomerates and consist of mechanical mixtures of crystals of the two enantiomers. Unfortunately, less than 20 percent of all racemates are conglomerates. The rest are true racemic compounds which cannot be separated by preferential crystallization (i.e., by seeding with the crystals of one enantiomer). A conglomerate exhibits a minimum melting point for the racemic mixture while a racemic compound shows a maximum melting point. The success of preferential crystallization depends on the fact that the two enantiomers crystallize at different rates and on the correlation between the melting point diagram and the solubility phase diagram, i.e., the mixture having the lowest melting point is the most soluble, and for a conglomerate this is the racemic mixture. Ibuprofen is a true racemic compound.
If the racemate is a true racemic compound, a homogeneous sold phase of the two enantiomers co-existing in the same unit cell, it may be separated via diastereomer crystallization, this generally involves reaction of the racemate with an optically pure acid or base (the resolving agent) to form a mixture of diastereomeric salts which is separated by crystallization.
Diastereomer crystallization is widely used for the industrial synthesis of pure enantiomers. A typical example is the Andeno process for the manufacture of (D)-(-)-phenylglycine, an antibiotic intermediate, using optically pure camphor sulfonic acid as the resolving agent.
The theoretical once-through yield of a resolution via diastereomer crystallization is 50 percent. However, in practice, a single recrystallization produces a composition that is simply an enantiomerically enriched racemate.
Another method for the resolution of racemates is kinetic resolution, the success of which depends on the fact that the two enantiomers react at different rates with a chiral addend.
Kinetic resolutions can also be effected using chiral metal complexes as chemocatalysts, e.g., the enantioselective rhodium-BINAP-catalyzed isomerization of the chiral allylic alcohol to the analogous prostaglandin intermediates reported by Noyori.
The enantioselective conversion of a prochiral substrate to an optically active product, by reaction with a chiral addend, is referred to as an asymmetric synthesis. From an economic viewpoint, the chiral addend functions in catalytic quantities. This may involve a simple chemocatalyst or a biocatalyst. An example of the former is the well-known Monsanto process for the manufacture L-dopa by catalytic asymmetric hydrogenation. See Knowles, et al., J. Am. Chem. Soc., 97, 2567 (1975). An example of the latter is the Genex process for the synthesis of L-phenylalanine by the addition of ammonia to transcinnamic acid in the presence of L-phenylalanine ammonia lyase (PAL). See Hamilton et al., Trends in Biotechnology, 3, 64-68, (1985).
With the exception of the preferential crystallization process, when applied to ibuprofen the prior art processes typically produce a first mixture that is essentially an enantiomerically enriched racemic composition. A number of crystallizations are required to yield the substantially pure enantiomer.